Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes

Abstract

Rearrangements in the anaplastic lymphoma kinase (<i>ALK</i>) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALK+ NSCLC and investigate its relationship with response to crizotinib. Using whole-exome sequencing and RNAseq data, we identified four rare ALK fusion partners (<i>HIP1, GCC2, ERC1</i>, and <i>SLC16A7</i>) and one novel partner (<i>CEP55</i>). At the mutation level, <i>TP53</i> was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of <i>ALK</i> or gain in <i>EGFR</i> was associated with shorter PFS. This study is the first to report a comprehensive view of the ALK+ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of <i>TP53</i> mutation as a strong prognostic indication of poor clinical response in ALK+ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALK+ NSCLC.